WO2007067619A2 - Certains types d'entites chimiques, compositions et methode de modulation de trpv1 - Google Patents

Certains types d'entites chimiques, compositions et methode de modulation de trpv1 Download PDF

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Publication number
WO2007067619A2
WO2007067619A2 PCT/US2006/046549 US2006046549W WO2007067619A2 WO 2007067619 A2 WO2007067619 A2 WO 2007067619A2 US 2006046549 W US2006046549 W US 2006046549W WO 2007067619 A2 WO2007067619 A2 WO 2007067619A2
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Prior art keywords
optionally substituted
alkyl
chosen
phenyl
chemical entity
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PCT/US2006/046549
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English (en)
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WO2007067619A3 (fr
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Jose S. Mendoza
Carl Nicholas Hodge
John K. Dickson, Jr.
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Amphora Discovery Corporation
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Publication of WO2007067619A3 publication Critical patent/WO2007067619A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms

Definitions

  • capsaicin analogs as analgesic agents.
  • capsazepine a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPVl receptors are also localized on sensory afferents which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.
  • R a and Rb are independently chosen from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that R 3 and Rb are not both hydrogen.
  • tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • Substituted carbamimidoyl refers to the group where R e , is chosen from: hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and R ⁇ and RS are independently chosen from: hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that at least one of R e , R ⁇ , and
  • R c is independently chosen from hydrogen and optionally substituted C1-C4 alkyl
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from
  • -C(O)Ci-C 4 alkyl -C(O)Ci-C 4 phenyl, -C(O)Ci-C 4 haloalkyl, -OC(O)Ci-C 4 alkyl, - SO 2 (Ci-C 4 alkyl), ⁇ SO 2 ( ⁇ henyl), -SO 2 (Ci-C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NH(Ci-C 4 alkyl), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHSO 2 (phenyl), and -NHSO 2 (Ci-C 4 haloalkyl).
  • Haloalkyl indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5- pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "- idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl, cycl ⁇ alkyl, or heterocycloalkyl, as defined herein
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O " ) substituents, such as pyridinyl N-oxides.
  • heterocycloalkyl is meant a single, non-aromatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1 -3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-pi ⁇ eridyl, 3- piperidyl, 4-piperidyl, and 2,5-piperizinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3 -morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3
  • modulation refers to a change in activity as a direct or indirect response to the presence of compounds of Formula I, relative to the activity of in the absence of the compound.
  • the change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the receptor, or due to the interaction of the compound with one or more other factors that in turn affect receptor activity.
  • the presence of the compound may, for example, increase or decrease receptor activity by directly binding to the receptor, by causing (directly or indirectly) another factor to increase or decrease the receptor activity, or by (directly or indirectly) increasing or decreasing the amount of receptor present in the cell or organism.
  • sulfonyl includes the groups: -S(0 2 )-(optionally substituted (Ci-
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • alkoxycarbonyl such as -C ⁇ 2 R b
  • aminocarbonyl such as
  • R a is chosen from optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from hydrogen, optionally substituted Ci -C ⁇ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, C 1 -C 4 haloalkyl, -OC]-C 4 alkyl,
  • substituted acyl refers to the groups (substituted alkyl)-C(O)-;
  • substituted heterocycloalkyl C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • alkoxycarbonyl such as -CO 2 R b
  • aminocarbonyl such as
  • R a is chosen from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., - ⁇ -(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • alkoxycarbonyl such as -CO 2 R b
  • aminocarbonyl such as
  • R a is chosen from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from H, optionally substituted C 1 -Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, arid optionally substituted heteroaryl; and
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Cj-C 4 alkyl, aryl, heteroaryl, aryl-CrC 4 alkyl-, heteroaryl-Q-d alkyl-, Cj-C 4 haloalkyl, -OCi-C 4 alkyl,
  • a substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH 2 CH 2 OCH3, and residues of glycol ethers such as polyethyleneglycol, and -0(CH 2 CH 2 O) x CHs, where x is an integer of 2-20, such as 2-10, and for example, 2-5.
  • Another substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2 ) y OH, where y is an integer of 1-10, such as 1-4.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-
  • R a is chosen from optionally substituted Ci -C O alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted C 1 -Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted
  • heterocycloalkyl group where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C4 alkyl, aryl, heteroaryl, OTyI-C 1 -C 4 alkyl-, heteroaryl-Ci -C 4 alkyl-, C 1 -C 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2 , -Ci-C 4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(Ci-C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkyl)(Ci-C 4 alkylpheny
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR c CO 2 R a , -NR°CONR b R°, - NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R b ), aminocarbonyl (such as -CONR b R c ), -OCOR b , -OCO 2 R 8 , -OCONR 15 R 0 , sulfanyl (such as SR b ), sulfin
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as 'one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, OTyI-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCi-C 4 alkyl, -OCi-C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -Od-C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 aIkyl-NH 2 , -N(C 1 -C 4 alkyl)(d-C 4 alkyl), -NH(Ci-C 4 alkyl), -N(C 1 -C 4 alkyl)(C r C 4 alkylphenyl),
  • substituted amino also refers to N-oxides of the groups -NHR d .
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • the person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • Compounds of Formula I include, but are not limited to, optical isomers of compounds of Formula I, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • compounds of Formula I include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds of Formula I exists in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.
  • Chemical entities of the present invention include, but are not limited to compounds of Formula I and all pharmaceutically acceptable forms thereof.
  • Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • Cosmetically acceptable forms of the compounds receited herein include cosmetically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the compounds described herein are in the form of pharmaceutically or cosmetically acceptable salts.
  • the terms "chemical entity” and “chemical entities” also encompass salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • Cosmetic refers to articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance.
  • Cosmetically acceptable refers to generally recognized as suitable for use for cosmetic purposes for humans, see, for example, International Cosmetic Ingredient Dictionary, published by the Cosmetic, Toiletry, and Fragrance Association, Inc.
  • Cosmetically acceptable carrier refers to any substantially non-toxic carrier conventionally useable for topical administration of cosmetics in which the compositions will remain stable and bioavailable when applied directly to the skin surface.
  • Suitable cosmetically acceptable carriers include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like.
  • carboxymethyl cellulose and salts with inorganic acids such as the hydrohalic acids (e.g., hydrochloric acid), sulfuric acid or phosphoric acid.
  • cosmetically effective amount of a chemical entity of this invention means an amount effective, when administered to a human, to provide a cosmetic benefit and includes an amount whereby the subject's skin is cosmetically treated
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
  • cyclopentanepropionic acid glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • ethanesulfonic acid 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
  • “Pharmaceutically acceptable excipient, carrier or adjuvant” refers to an excipient, carrier or adjuvant that can be administered to a subject, together with at least one chemical entity of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which at least one chemical entity of the present disclosure is administered.
  • active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • inhibitors indicates a significant decrease in the baseline activity of a biological activity or process.
  • Treatment means any treatment of a disease in a patient, including: a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
  • Patient refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment.
  • the methods of the invention can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
  • R 2 is not chosen from cyano, halo, methoxy, ethoxy, methyl, n-butyl, dimethylamino, and trifluoromethyl.
  • R 1 is chosen from hydrogen and optionally substituted alkyl. In some embodiments, R 1 is chosen from hydrogen and optionally substituted lower alkyl. In some embodiments, R 1 is chosen from hydrogen and lower alkyl. In some embodiments, R 1 is hydrogen.
  • L is -C(O)-. [089] In some embodiments, L is -S(O) 2 -.
  • R 2 is chosen from nitro, halo, hydroxy, optionally substituted alkoxy, and optionally substituted alkyl.
  • R 2 is chosen from nitro, halo, hydroxy, optionally substituted lower alkoxy, and optionally substituted lower alkyl.
  • the methods described herein comprise administering at least one chemical entity chosen from
  • Chemical entities of the present disclosure can be prepared by methods well known in the art. Chemical entities of the present disclosure can be prepared from readily available starting materials using the flowing general methods and procedures. It will be appreciated that where typical or preferred process conditions, such as, reaction temperatures, times, mole ratios of reactants, solvents, pressures, are given, other process conditions can also be used unless otherwise stated. Reaction conditions may vary with the reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [096] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, 1999, and references cited therein.
  • the hexafluoro-2-phenylpropan ⁇ 2-ol compounds I of the present invention can be prepared using aniline derivatives of structure 1.
  • Acylation or sulfonylation of anilines 1 to provide I can be achieved by methods known in the art, such as those described in PCT application WO 00/54759, which is incorporated herein by reference..
  • structure 1 which may serve as starting materials are commercially available or can be prepared according to known literature methods.
  • the present disclosure relates to methods of treating a disease regulated by TRPVl in a subject.
  • diseases or disorders that are known or believed to be regulated by TRPVl include:
  • Pain including action on small sensory nerve fibers to inhibit, counteract, mask, attenuate or otherwise reduce the activation, transmission, or integration of the neuronal signal for somatic, visceral and neuropathic pain, such as nociceptive pain, neurogenic pain, pain associated with chronic peripheral polyneuropathy, neuropathic pain, postmastectomy pain syndrome, stump pain after amputation, phantom limb pain, oral neuropathic pain, toothache, postherpetic neuralgia, pain associated with diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, fibromyalgia, pain associated with Guillain-Barre syndrome, Charcot's pain, Crohn's Disease, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropathy, spinal
  • A.delta. sensory nerves and epithelium in the bladder and ureter such as bladder overactivity, hyperactive urinary bladder, hypersensitive urinary bladder, interstitial cystitis, painful bladder disorders, and urinary incontinence.
  • Obstructive Breathing Disorders including action on the sensory nerves that mediate the sensations of breathing disorders, for example to cause refreshed breathing, less sneezing and throat irritation, less cough, decreased inspiratory effort, and relief of dyspnea, for example, the treatment of cough, hiccup, bronchial asthma, or chronic obstructive pulmonary disease.
  • Bowel Dysfunction including counteracting the pain and discomforts of gut discomfort and inflammation, for example, by reducing intestinal perception of noxious signals by blocking the afferent nerve receptors, for example, treating the symptoms of enteritis, colitis, and proctitis, caused by conditions such as irritable bowel disease, irritable bowel syndrome, intestinal gas, the side-effects of prostate brachytherapy, and other forms of gastrointestinal dysfunction.
  • Allergy or autoimmune disease such as rheumatoid arthritis, conjunctivitis, rhinitis, sinusitis and otitis media with effusion.
  • noxious sensory disorders include, but are not limited to, heat exhaustion, the flushing sensations of menopause and fatigue.
  • TRP V 1 can be modulated by contact with at least one chemical entity of the present disclosure.
  • Jn vivo TRPVl can be modulated by administration through routes and using compositions comprising at least one chemical entity of the present disclosure.
  • contacting TRPVl with at least one chemical entity of the present disclosure can include, for example, combining liquid reagents or combining a reagent and TRPVl and/or chemical entityof the present disclosure attached to a solid support.
  • the TRPVl and at least one chemical entity of the present disclosure can be contacted in any appropriate device such as an affinity chromatography column, a microarray, a W
  • compositions of the present disclosure can contain one or more pharmaceutically acceptable vehicles.
  • the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or the delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, interasynovial, intrasternal, interathecal, intralesional, and intracranial injection or infusion techniques.
  • compounds disclosed herein can be delivered orally. Suitable dosage ranges for oral administration can depend on the potency of the compounds, but generally can range from 0.1 mg to 20 mg of a compound per kilogram of body weight.
  • Appropriate dosages can be in the range of 25 to 500 mg/day and the dose of compounds administered can be adjusted to provide an equivalent molar quantity of compound in the plasma of a subject. Dosage ranges can be readily determined by methods known to those skilled in the art.
  • Chemical entities of the present disclosure can be assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity prior to therapeutic use in mammals.
  • in vitro assays can be used to determine whether administration of a specific chemical entity of the present disclosure or a combination of such chemical entities is effective for modulating the activity of TRPVl or treating at least one disease.
  • Chemical entities of the present disclosure can also be demonstrated to be effective and safe using animal model systems.
  • a therapeutically effective dose of at least one chemical entity of the present disclosure can, in certain embodiments, provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of chemical entities of the present disclosure can be determined using standard pharmaceutical procedures and can be readily ascertained by the skilled artisan.
  • the dose ratio between toxic and therapeutic effect is the therapeutic index.
  • Chemical entities of the present disclosure can exhibit high therapeutic indices in treating diseases and disorders.
  • the dosage of a compound of the present present disclosure can be within a range of circulating concentrations that include an effective dose with little or no toxicity.
  • compositions When employed as pharmaceuticals, chemical entities of the present disclosure can be administered in the form of pharmaceutical compositions.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and can comprise at least one chemical entity of the present disclosure.
  • compositions of the present disclosure can comprise a
  • compositions of the present disclosure can additionally comprise at least addional compound that enhances the therapeutic efficacy of one or more chemical entities of the present disclosure. For example, such compounds
  • compounds can enhance the therapeutic efficacy of chemical entities of the present disclosure by effectively increasing the plasma concentration of the compounds.
  • certain compound can decrease the degradation of the chemical entities of the present disclosure prior to administration or during transport to the plasma, or within the plasma.
  • a pharmaceutical composition can include at least one chemical entity of the present disclosure and at least one additional therapeutic agent appropriate for effecting combination therapy.
  • compositions that contain, as the active ingredient, of one or more chemical entities of the present disclosure associated with pharmaceutically acceptable excipients.
  • the active ingredient can be mixed with an excipient, diluted by an excipient, or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent
  • the excipient can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the active compound In preparing a composition, it can be necessary to mill the active compound to provide the appropriate particle size prior to combining with other ingredients. If the active compound is insoluble, the active component ordinarily can be milled to a particle size of less than 200 mesh. If the active compound is water soluble, the particle size can be adjusted by milling to provide a uniform distribution in the formulation, e.g. 40 mesh.
  • compositions can additionally include, lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxy- benzoates, sweetening agents, and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy- benzoates
  • sweetening agents and flavoring agents.
  • Compositions of the present disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature.
  • the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature.
  • compositions of the present disclosure can be selected for parenteral delivery. In other embodiments, compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art. [0132] In certain embodiments, composition components can be present in
  • a pharmaceutical composition can be formulated for inhalation.
  • a compound of the present disclosure, with or without at least one additional therapeutic agent can be formulated as a dry powder for inhalation.
  • an inhalation solution comprising a compound of the present disclosure with or without at least one additional therapeutic agent can be formulated with a propellant for aerosol delivery.
  • solutions can be nebulized.
  • solutions, powders or dry films of chemical entities of the present disclosure can be aerosolized or vaporized for pulmonary delivery.
  • formulations can be administered orally.
  • a compound of the present disclosure, with or without at least one additional therapeutic agent that can be administered orally can be formulated with or without carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation in the region of the gastrointestinal tract where bioavailability can be maximized and pre-systemic degradation minimized.
  • at least one additional agent can be included in the formulation to facilitate absorption of the compound of the present disclosure and/or any additional therapeutic agents into the systemic circulation.
  • diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can be employed.
  • a pharmaceutical composition of the present disclosure can include an effective quantity of chemical entities of the present disclosure, with or without at least one additional therapeutic agent, in a mixture with at least one pharmaceutically acceptable vehicle suitable for the manufacture of tablets.
  • suitable excipients include inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the frequency of dosing will take into account the pharmacokinetic parameters of the chemical entities of the present disclosure and/or any additional therapeutic agents in the pharmaceutical composition used.
  • a clinician can administer the composition until a dosage is reached that achieves the desired effect.
  • the composition can be administered as a single dose, or as two or more doses, which may or may not contain the same amount of the therapeutically active compound time, or as a continuous infusion via an implantation device or catheter. Further refinement of an appropriate dosage can be routinely made by those of ordinary skill in the art. For example, therapeutically effective amounts and regimens can be determined through use of appropriate dose-response data.
  • a pharmaceutical composition comprising a compound of the present disclosure, with or without at least one additional therapeutic agent, in an ex vivo manner.
  • cells, tissues and/or organs that have been removed from a subject are exposed to a pharmaceutical composition comprising a compound of the present disclosure, with or without at least one additional therapeutic agent, after which the cells, tissues and/or organs are subsequently implanted back into the subject.
  • compositions according to the present disclosure can take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • administration is topical to inflamed skin or mucous membranes, and the therapeutic effectiveness is in relieving itch, irritation or pain.
  • compositions of the present disclosure can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device can be accompanied by instructions for
  • the quantity of a compound of the present disclosure required for the treatment of a particular condition can vary depending on the compound, and the condition of the subject to be treated.
  • daily dosages can range from 100 ng/kg to 100 mg/kg, e.g., 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration; from 10 ng/kg to 50 mg/kg body weight, e.g., 0.001 mg/kg to 20 mg/kg body weight, for parenteral administration; and from 0.05 mg to 1 ,000 mg for nasal administration or administration by inhalation or insufflation.
  • Certain chemical entities of the present disclosure and/or compositions of the present disclosure can be administered as sustained release systems.
  • the chemical entities of the present disclosure can be delivered by oral sustained release administration.
  • the chemical entities of the present disclosure can be administered, for example, twice per day and, once per day.
  • sustained and/or extended release dosage forms include, but are not limited to, beads comprising a dissolution or diffusion release compositon and/or structure, an oral sustained release pump, enteric-coated preparations, compound-releaseing lipid matrices, compound releasing waxes, osmotic delivery systems, bioerodible polymer matrices, diffusible polymer matrices, a plurality of time-release pellets, and osmitic dosage forms.
  • sustained release oral dosage forms can provide a therapeutically effective amount of a compound of the present disclosure over a period of at least several hours.
  • the extended release dosage form can provide a constant therapeutically effective concentration of a compound of the present disclosure in the plasma of a subject for a prolonged period of time, such as at least several hours.
  • the sustained release oral dosage form can provide a controlled and constant concentration of a therapeutically effective amount of a compound of the present disclosure in the plasma of a subject.
  • Dosage forms comprising compositions and chemical entities of the present disclosure can be administered at certain intervals such as, for example, twice per day or once per day.
  • Exemplary dosage ranges for oral administration are dependent on the potency of the compound of the present disclosure, but can range from 0.1 mg to 20 mg of the compound per kilogram of body weight. Dosage ranges may be readily determined by methods known to those skilled in the art.
  • packaged pharmaceutical formulations include a pharmaceutical composition comprising at least one chemical entity of the present disclosure, and instructions for using the composition to treat a mammal (typically a human patient).
  • the instructions are for using the pharmaceutical composition to treat a patient suffering from a disease responsive to modulation of TRPVl.
  • prescribing information for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • a cosmetic composition comprising a cosmetically effective amount of at least one chemical entity described herein and at least one cosmetically acceptable carrier.
  • the cosmetic composition is chosen from an after-sun product, a pre-shave product, an after-shave product, a pre-depilation product and an after-depilation product.
  • Chemical entities of the present disclosure can be assayed in vitro and in vivo, to determine and optimize therapeutic or prophylactic activity prior to use in subjects. For example, in vitro assays can be used to determine whether administration of a specific compound of the present disclosure or a combination of such compounds exhibits therapeutic efficacy. Chemical entities of the present disclosure can also be demonstrated to be effective and safe using animal model systems.
  • Embodiments of the present disclosure can be further defined by reference to the following examples, which describe in detail preparation of chemical entities of the present disclosure and assays for using chemical entities of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the present disclosure.
  • MS ions were detected using a Sciex API-100 electrospray single quadrupole mass spectrometer interfaced to the HPLC system.
  • TRPVl mammalian expression system A variety of molecular engineering strategies can be employed to express functional TRPVl protein in mammalian cell systems.
  • the gene encoding human TRPVl (GenBank Accession No. AFl 96175) was subcloned into a suitable vector to generate BacMam virus that was subsequently used to infect HEK293 cells (also expressing the Ebstein Barr Virus Nuclear Antigen or EBNA) to induce expression of constitutively active human TRPVl protein.
  • HEK293/EBNA cells were cultured in Dulbecco's Modified Eagle Medium

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des entités chimiques choisies parmi des composés de formule (I) et sur des sels acceptables d'un point de vue pharmaceutique ou cosmétique, des solvates, des chélates, des complexes non covalents, des promédicaments et des mélanges de ceux-ci. Les entités chimiques modulent TRPV1 et sont utiles dans le traitement d'au moins une maladie ou trouble modulé par l'activité de TRPV1.
PCT/US2006/046549 2005-12-08 2006-12-05 Certains types d'entites chimiques, compositions et methode de modulation de trpv1 WO2007067619A2 (fr)

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US60/748,878 2005-12-08

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009128661A2 (fr) 2008-04-18 2009-10-22 주식회사 대웅제약 Nouveau dérivé de benzoxazine benzimidazole, composition pharmaceutique le comprenant et application s'y rapportant
US8026235B1 (en) 2010-10-13 2011-09-27 Daewoong Pharmaceutical Co., Ltd. Pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096358A1 (en) * 2002-03-28 2005-05-05 Yang Gao Substituted biaryl amides as C5A receptor modulators
US20050159394A1 (en) * 2003-12-31 2005-07-21 Wei Edward T. Aryl-substituted derivatives of cycloalkyl and branched chain alkyl carboxylic acids useful as antinociceptive drugs for peripheral targets

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050096358A1 (en) * 2002-03-28 2005-05-05 Yang Gao Substituted biaryl amides as C5A receptor modulators
US20050159394A1 (en) * 2003-12-31 2005-07-21 Wei Edward T. Aryl-substituted derivatives of cycloalkyl and branched chain alkyl carboxylic acids useful as antinociceptive drugs for peripheral targets

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
WO2009128661A2 (fr) 2008-04-18 2009-10-22 주식회사 대웅제약 Nouveau dérivé de benzoxazine benzimidazole, composition pharmaceutique le comprenant et application s'y rapportant
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
US8026235B1 (en) 2010-10-13 2011-09-27 Daewoong Pharmaceutical Co., Ltd. Pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof

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